A joint project of the Graduate School, Peabody College, and the Jean & Alexander Heard Library

Title page for ETD etd-01112019-155241


Type of Document Dissertation
Author Burman, Ankita
Author's Email Address burman.ankita@gmail.com
URN etd-01112019-155241
Title Unraveling the Role of Endoplasmic Reticulum Stress in Idiopathic Pulmonary Fibrosis (IPF)
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Chin Chiang Committee Chair
Mark deCaestecker Committee Member
Timothy S. Blackwell Committee Member
Volker Haase Committee Member
Keywords
  • UPR
  • IPF
  • ER stress
  • Pulmonary. Fibrosis
  • Lung
Date of Defense 2018-11-19
Availability unrestricted
Abstract
Endoplasmic reticulum (ER) stress in type II AECs has been associated with pathogenesis of IPF; however, factors inducing ER stress and downstream mechanisms through which ER stress impacts phenotype of type II AECs are not well-understood. We identified localized hypoxia in type II AECs in a repetitive bleomycin-induced lung fibrosis mouse model as a potential mechanism explaining ER stress. We found that C/EBP homologous protein (CHOP), a downstream effector in the ER stress pathway, increases apoptosis of type II AECs and augments fibrosis in 3 separate mouse models. In vitro studies in mouse lung epithelial (MLE12) cells showed that the unfolded protein response (UPR) pathways Inositol-Requiring Enzyme 1α (IRE1α)/X-box Binding Protein 1 (XBP1) and PKR-like ER kinase (PERK)/Activating Transcription Factor 4 (ATF4) regulate CHOP in type II AECs in hypoxia. CHOP regulates hypoxia-induced apoptosis of type II AECs through several pro-apoptotic downstream mediators. On investigating the role of Hypoxia-Inducible Factor (HIF), we found that while epithelial HIF signaling did not affect lung fibrosis after single dose bleomycin treatment or bleomycin treatment followed by exposure to hypoxia, it was important in exacerbation of fibrosis after repetitive bleomycin injury in mice. In human IPF samples, we found prominent expression of both CHOP and markers of hypoxia in type II AECs, supporting the idea of hypoxia-induced ER stress in IPF.
Files
  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
  Burman.pdf 4.40 Mb 00:20:23 00:10:29 00:09:10 00:04:35 00:00:23

Browse All Available ETDs by ( Author | Department )

If you have more questions or technical problems, please Contact LITS.